Genetics of multi system disorders Flashcards
Which mode of inheritance for trisomy 21?
Chromosomal
Which mode of inheritance for TS?
Autosomal dominant
Which mode of inheritance for NF1?
Autosomal dominant
Which mode of inheritance for Myotonic dystrophy?
Autosomal dominant
Which mode of inheritance for cystic fibrosis?
Autosomal recessive
Which mode of inheritance for Duchenne muscular dystrophy?
X-linked
Types of Chromosomal disorders?
> Numerical eg trisomy 21
> Structural eg translocations, deletions and micro deletions
Types of single gene disorders?
> Autosomal dominant eg TS, NF1, myotonic dystrophy
> Autosomal recessive eg Cystic fibrosis
> X-linked eg Duchenne muscular dystrophy
Types of multifactorial disorders?
> Polygenic
> Environmental factors:
- Haemochromatosis - Diabetes
Why multi-system involvement?
1) Several genes with diverse functions are involved (chromosomal)
2) Single gene widely expressed in different tissues
3) Single gene tissue-specific expression but tissue integral part of many different systems
Common problems in multi-system disease?
1) Variable expression within as well as between families
2) Present to a large variety of different specialists
3) Family history easily missed
What is the inheritance of neurofibromatosis type 1 (NF1)?
Autosomal Dominant
What is the prevalence of neurofibromatosis type 1 (NF1)?
Prevalence 1/2500-3500
What is the diagnostic criteria for neurofibromatosis type 1 (NF1)?
Requires 2 or more: 1) Café au lait spots - 6 or more 2) Neurofibromas - 2 or more axillary freckling 3) Lisch nodules (specks in iris) 4) Optic glioma 5) Thinning of long bone cortex 6) Family history
Features of neurofibromatosis type 1 (NF1)?
1) Café au lait spots - 6 or more
2) Neurofibromas - 2 or more
axillary freckling
3) Lisch nodules (specks in iris)
4) Optic glioma
5) Thinning of long bone cortex
6) Macrocephaly
7) Short stature
8) Dysmorphic features- “Noonan look”
9) Learning difficulties
10) Epilepsy
11) Scoliosis
12) Pseudoarthrosis of the tibia
13) Raised BP - due to renal artery stenosis or phaechromocytoma
14) Neoplasia - CNS (optic gliomas), endocrine
Management of neurofibromatosis type 1 (NF1)?
> Annual review of affected individuals and at risk children until diagnosis can be excluded (5 years)
> BP
> Spine for scoliosis
> Tibia for unusual angulation
visual acuity and visual fields
> Educational assessment
> Ask patient to report any unusual symptoms
Which gene is the cause of neurofibromatosis type 1 (NF1)?
Loss or mutation of 17q - A tumour suppressor gene
50% of cases of neurofibromatosis type 1 (NF1) are due to new mutations, what is the origin usually?
Usually paternal in origin
What are the main features of neurofibromatosis type 1 (NF2)?
1) Acoustic neuromas - usually bilateral
2) CNS and spinal tumours
3) A few CAL spots
What is the mutation of NF2?
NF2 gene on chromosome 22
What is the incidence of Tuberous Sclerosis (TS)?
1 in 7000
What are the main features of tuberous sclerosis?
The classic triad:
1) Epilepsy, in 65%:
- Infantile spasms
- Myoclonic seizures
2) Learning difficulty in 40%:
- Autistic features are common
3) Skin lesions:
- Depigmented macules
- Angiofibromas
- Fibrous plaque forehead
- Shagreen patches
- Ungual fibromas
- Focal Hypopigmentation
Harmartomas in different organs:
- Kidney = Cysts and angiomyolipomata
- Phakomas in eye, benign unless on macula
- Heart = Rhabdomyomas
- CNS = Cortical tubers, sub-ependymal nodule, astocytomas
What os the mode of inheritance of Tuberous sclerosis (TS)?
Autosomal dominant - 60% are due to new mutations
Almost full penetrance - Gene carriers will have some signs even if only on scans
What is meant by variable expression in Tuberous sclerosis?
Severity varies between family members
Which genes are the cause of Tuberous Sclerosis?
2 genes on different chromosomes both cause TS with identical phenotypes:
> TSC1
> TSC2
Clinical examination in Tuberous sclerosis (Screening tools)?
> Skin signs, including Woods lamp, nails
> Retinal examination
Screening tools in Tuberous sclerosis?
1) Clinical examination
- Skin signs, including Woods lamp, nails
- Retinal examination
2) Cranial MR scan
3) Renal ultrasound
4) Echocardiogram
Mode of inheritance for myotonic dystrophy?
Autosomal dominant
Mutation which leads to myotonic dystrophy?
CTG repeat, exhibits anticipation with increasing severity in each generation
Presentation features of myotonic dystrophy?
1) Bilateral late-onset cataract
2) Muscle weakness, stiffness & myotonia
- Facial features
- Trapezius, forearms, lower leg and diaphragm affected
3) Low motivation, bowel probs, diabetes mellitus
4) Heart block
5) Death post-anaesthetic a risk if not monitored
6) Congenital myotonic dystrophy:
- Death
- Severe muscle disorder
- Learning difficulty
Things to remember in multi-system genetic disorders?
> Treat the whole patient
> Role for co-ordinating specialist
> Regular follow up if clinically beneficial
> Remember reproductive counselling
> Variable expression
> Understanding natural history allows early management of complications
